Pyrazine derivatives



United States Patent Ofiice 3,501,464 Patented Mar. 17, 1970 US. Cl.260239.7 3 Claims ABSTRACT OF THE DISCLOSURE Our present inventionrelates to new pyrazine derivatives having antibacterial activity and tothe preparation thereof. More particularly, our invention has as anobject Z-sulfanilamido-pyrazine-4-oxide (I) andZ-sulfanilamido-pyrazine-l-oxide (II) which have the followingstructural formula:

The products of the invention have a high antibacterial activity ongram-positive and gram-negative schizomycetes and a very low toxicity soas to be usefully employed in human and veterinary therapy.

Pyrazine sulfamides having antibacterial activity are described in theliterature. It was an object of the present invention to find newpyrazine derivatives, which besides having a high antibacterial activityand a toxicity lower than that of the known analogous compounds, have aremarkable elimination ratio which makes them useful in sulfamidictherapy where the use of products having a non-delayed action isrecorded.

The new products of the invention, 2-sulfanilamidopyrazine 4-oxide (I)and 2-sulfanilamidopyrazine-l-oxide (ll), are prepared by condensationof 2-chloro-pyrazine- 4oxide and -l-oxide respectively withsulfanilamide in the presence of a base, such as potassium carbonate, atabout the melting point of the mixture, or by condensation with asulfanilarnide alkali salt in the presence of a solvent, such asacetamide, at the temperature of 150" C. By subsequent acidification,the product thus obtained precipitates. The product is then isolated andpurified by the known separation and purification techniques.

The following examples serve to illustrate the invention withoutlimiting it.

EXAMPLE 1 Z-sulfanilamidopyrazine-4-oxide (I) 1 mol of2-chloropyrazine-4oxide (L. Bernardi et a1. Gazz. Chim. Ital. 91 (1961),page 1435) is mixed with 1.5 mols of sulfanilamide and 0.82 mol ofpotassium carbonate. The mixture is kept at the melting point of C. forfrom 4 to 6 hours. When the reaction is over, the mixture is dilutedwith 200 cc. of water and it is acidified to pH 3.5 with 4 N HCl. Thesolid compound which precipitates is separated by filtration, washedwith water and dried. 2-sulfanilamido-pyrazine-4-oxide, melting at 235-240 C., is obtained in a yield of 70% with respect to the starting2-chloropyrazine 4 oxide. By recrystallization from ethanol, the productobtained melts at 240-241 C. Unreacted 2-chloropyrazine-4-oxide isrecovered from the mother liquors by extraction with chloroform.

EXAMPLE 2 2-sulfanilamidopyrazine-l-oxide (11) Operating as in Example1, but using 2-chloropyrazinel-oxide (Bernardi et al. Gazz. Chim. Ital.91, (1961), p. 1435) 2-sulfanilamidopyrazine-l-oxide melting at 220- 221C. is obtained. Recrystallization from dioxane gives a product meltingat 222 C.

The antibacterial activity of the products of the invention has beendetermined according to the tests described hereinbelow. The results ofthe tests are reported in tables in comparison with results obtainedwith the known sulfamide drug sulfamethopyrazine (2-sulfanilamido-3-methoxy-pyrazine) described by B. Camerino et al., US. Patent 3,098,069.

Table 1 reports the values of the 50% inhibition dose (ID in vitro,expressed in g. per cc. of liquid medium having the compositiondescribed by Capps et al., J. Bact. 55 (1948), p. 869. The ID indicatesthe concentration capable of reducing 50% of the development of thetreated bacteria in respect to the controls.

Tests of the therapeutical activity of the products of the inventionhave been carried out on mice experimentally infected by intraperitonealroute with Staphylococcus aureus Camp, Salmonella abortivo-cquina andPlasmodt'um berghei. The products have been administered orally by onetreatment daily.

Table 2 reports the following obtained values:

TABLE 2 Dose, Days of TDm Infection Compound mgJkg. treatment LIR mgJkg.Tl.

Staphylococci mucus I 200 Camp. 50100200 Sulpharnetho- 200 pyrazino.50-100-200 Salmonella abortz'vo- I 200 equine. 50100-200 II 25-50-l00Sulphametho- 200 pyrazine. 50-100-200 Plas'modium I 25-100-400 l 80 B1.2 berghei. 6. 2525-100 6 10 650 Sulphametho- 25400-400 1 7a 22. 6pyruzlne. 6.25-25-100 5 6.25 272 Plasmodium II 25-100-400 1 1200berphet. 6. -25-100 5 Sulphametho- 25-100-400 1 400 4. 25 pyrazine. 6.25-25-100 5 12 141. 6

L T treated animals) LTMcontrols) wherein LT is the time within which50% of the animals die.

TD =therapeutic dose, expressed in mg./kg. of body weight, whichadministration causes a recovery of 50% of the treated animals.

therapeutic index expressed by the ratio between the lethal dose 50 (LDthat is the dose in mg./kg. able to cause the death of 50% of thetreated animals, and the therapeutic dose 50.

The toxicity of 2-sulfanilamido-pyrazine-4-oxide intravenouslydetermined in the mouse, and expressed as LD is 6.5 g./kg., while thatof sulfamethopyrazine is 1.7 g./kg. and that of sulfapyrazine is 0.630g./kg.

Table 3 reports the values of therapeutical activity (expressed as ratioLTR of the products of the invention in comparison to sulfapyrazine andto sulfamethopyrazine in the experimental infection of mice withDiplococcus pneumoniae, by carrying out only one treatment with theproducts under examination at the dose of 200 mg./kg. The infectionshave been carried out at various intervals, namely after 8, 24 and 48hours from the administration of the products.

As results from Table 3, the elimination ratio of the two new productsof the invention may be compared to that of sulfapyrazine while it ishigher than that of sulfamethopyrazine. The products of the inventionare useful in human and veterinary therapy. They are preferablyadministered by oral route, for instance in the form of powders,tablets, pills or capsules, in the presence of a suitable liquid orsolid excipient or other pharmacologically acceptable substance.

At least 10 animals were used in each of the tests as reported by thetables above.

We claim:

1. A compound selected from the group consisting of2-sulfanilamidopyrazine-4-oxide and 2-sulfanilamidopyrazine-l-oxide.

2. The compound of claim 1, which is 2-sulfanilamidopyrazine-toxide.

3. The compound of claim 1, which is 2-sulfanilamidopyrazine-l-oxide.

References Cited UNITED STATES PATENTS 3,098,069 7/1963 Camerino et a1.260239.7

HENRY R. JILES, Primary Examiner C. M. SHURKO, Assistant Examiner U.S.Cl. X.R.

